EP3151860B1 - Compositions biophotoniques thermodurcissables et utilisations correspondantes - Google Patents

Compositions biophotoniques thermodurcissables et utilisations correspondantes Download PDF

Info

Publication number
EP3151860B1
EP3151860B1 EP15805894.1A EP15805894A EP3151860B1 EP 3151860 B1 EP3151860 B1 EP 3151860B1 EP 15805894 A EP15805894 A EP 15805894A EP 3151860 B1 EP3151860 B1 EP 3151860B1
Authority
EP
European Patent Office
Prior art keywords
skin
thermosetting
composition
biophotonic composition
thermosetting biophotonic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP15805894.1A
Other languages
German (de)
English (en)
Other versions
EP3151860A4 (fr
EP3151860A1 (fr
Inventor
Remigio Piergallini
Nikolaos Loupis
Emmanuelle DEVEMY
Eric Desrosiers
Abdellatif Chenite
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Klox Technologies Inc
Original Assignee
Klox Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Klox Technologies Inc filed Critical Klox Technologies Inc
Publication of EP3151860A1 publication Critical patent/EP3151860A1/fr
Publication of EP3151860A4 publication Critical patent/EP3151860A4/fr
Application granted granted Critical
Publication of EP3151860B1 publication Critical patent/EP3151860B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/22—Peroxides; Oxygen; Ozone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/90—Block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/42—Colour properties
    • A61K2800/43—Pigments; Dyes
    • A61K2800/434—Luminescent, Fluorescent; Optical brighteners; Photosensitizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/48—Thickener, Thickening system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/81—Preparation or application process involves irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0651—Diodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0654—Lamps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A61N2005/0663—Coloured light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light

Definitions

  • Phototherapy has recently been recognized as having wide range of applications in both the medical and cosmetic fields including use in surgery, therapy and diagnostics.
  • phototherapy has been used to treat cancers and tumors with lessened invasiveness, to disinfect target sites as an antimicrobial treatment, to promote wound healing, and for facial skin rejuvenation (i.e. WO 2013/155620 ).
  • Photodynamic therapy is a type of phototherapy involving the application of a photosensitive agent to target tissue then exposing the target tissue to a light source after a determined period of time during which the photosensitizer is absorbed by the target tissue.
  • Such regimens are often associated with undesired side-effects, including systemic or localized toxicity to the patient or damage to non-targeted tissue.
  • such existing regimens often demonstrate low therapeutic efficacy due to, for example, the poor selectivity of the photosensitive agents into the target tissues.
  • thermosetting biophotonic compositions compositions for their use in therapy and methods useful in the cosmetic treatment of a target tissue.
  • thermosetting biophotonic composition of the invention comprises a block copolymer at a concentration of more than 20% weight per volume of the composition, the block copolymer comprising at least one sequence of polyethylene glycol-propylene glycol (PEG-PPG), polyethylene glycol-poly(lactic acid) (PEG-PLA) or polyethylene glycol-poly( ⁇ -caprolacone) (PEG-PCL), and at least one xanthene dye selected from Eosin Y, Erythrosine B, Fluorescein, Rose Bengal and Phloxin B, solubilized within the block copolymer, the at least xanthene dye being from 0.001% and 3% per weight of the composition, the thermosetting biophotonic composition being in liquid form at 22°C and thermosetting on exposure of heat.
  • PEG-PPG polyethylene glycol-propylene glycol
  • PEG-PLA polyethylene glycol-poly(lactic acid)
  • PEG-PCL polyethylene glycol-poly( ⁇ -cap
  • the block copolymer comprises at least one sequence of polyethylene glycol-propylene glycol (PEG-PPG). More particularly the block copolymer is a poloxamer.
  • PEG-PPG polyethylene glycol-propylene glycol
  • thermosetting biophotonic composition of the invention further comprises a stabilizer selected from gelatin, hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC) and a thickening agent.
  • a stabilizer selected from gelatin, hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC) and a thickening agent.
  • thermosetting biophotonic composition of the invention further comprises an oxidizing agent, wherein the oxidizing agent is selected from hydrogen peroxide, urea peroxide and benzoyl peroxide.
  • the present disclosure also provides for a method for cosmetic treatment of tissue, the method comprising: applying thermosetting biophotonic composition of the invention over a target skin tissue; and illuminating the thermosetting biophotonic composition with light having a wavelength that overlaps with the absorption spectrum of the at least one xanthene dye.
  • the cosmetic treatment of tissue may particularly be selected from skin rejuvenation, skin conditioning and promotion of collagen synthesis
  • thermosetting biophotonic composition for use in one of more of
  • the skin disorder may be selected from acne, eczema, psoriasis and dermatitis.
  • thermosetting biophotonic membranes and uses thereof. Biophotonic therapy using these compositions would combine the beneficial effects of thermosetting compositions with the photobiostimulation induced by the fluorescent light generated upon illumination of the composition. Furthermore, in certain embodiments, phototherapy using the thermosetting biophotonic compositions of the present disclosure will for instance rejuvenate the skin by, e.g., promoting collagen synthesis; promote wound healing or tissue repair; prevent or treat scars; treat skin conditions such as acne, eczema, psoriasis or dermatitis; or treat periodontitis.
  • the term "about” in the context of a given value or range refers to a value or range that is within 20%, preferably within 10%, and more preferably within 5% of the given value or range.
  • Biophotonic means the generation, manipulation, detection and application of photons in a biologically relevant context. In other words, biophotonic compositions exert their physiological effects primarily due to the generation and manipulation of photons.
  • Thermosetting means a liquid composition that can undergo a phase transition to a solid or a semi-solid state (e.g., a gel) spontaneously (e.g. on contact with a target tissue) or following exposure to some form of energy (e.g., heat energy).
  • the heat energy may be provided by contact with a warm body, or by a light source.
  • the phase transition to a solid or semi-sold state can occur on contact with a tissue which is at a higher temperature than the ambient temperature.
  • thermosetting and “thermogelling” are used herein interchangeably.
  • the terms “thermoset” and “thermogel” are also used herein interchangeably.
  • Topical application or “topical uses” means application to body surfaces, such as the skin, mucous membranes, vagina, oral cavity, internal surgical wound sites, and the like.
  • chromophore and "photoactivator” are used herein interchangeably.
  • a chromophore means a chemical compound, when contacted by light irradiation, is capable of absorbing the light. The chromophore readily undergoes photoexcitation and can transfer its energy to other molecules or emit it as light (e.g. fluorescence).
  • Photobleaching or “photobleaches” means the photochemical destruction of a chromophore.
  • a chromophore may fully or partially photobleach.
  • actinic light is intended to mean light energy emitted from a specific light source (e.g. lamp, LED, or laser) and capable of being absorbed by matter (e.g. the chromophore or photoactivator). In a preferred embodiment, the actinic light is visible light.
  • a specific light source e.g. lamp, LED, or laser
  • matter e.g. the chromophore or photoactivator
  • the actinic light is visible light.
  • actinic light and “light” are used herein interchangeably.
  • Skin rejuvenation means a process of reducing, diminishing, retarding or reversing one or more signs of skin aging or generally improving the condition of skin.
  • skin rejuvenation may include increasing luminosity of the skin, reducing pore size, reducing fine lines or wrinkles, improving thin and transparent skin, improving firmness, improving sagging skin (such as that produced by bone loss), improving dry skin (which might itch), reducing or reversing freckles, age spots, spider veins, reducing or preventing the appearance of rough and leathery skin, fine wrinkles that disappear when stretched, reducing loose skin, or improving a blotchy complexion.
  • one or more of the above conditions may be improved or one or more signs of aging may be reduced, diminished, retarded or even reversed by certain embodiments of the compositions, methods and uses of the present disclosure.
  • Wound means an injury to any tissue, including for example, acute, subacute, delayed or difficult to heal wounds, and chronic wounds. Examples of wounds may include both open and closed wounds. Wounds include, for example, amputations, burns, incisions, excisions, lesions, lacerations, abrasions, puncture or penetrating wounds, surgical wounds, amputations, contusions, hematomas, crushing injuries, ulcers (such as for example pressure, diabetic, venous or arterial), scarring, and wounds caused by periodontitis (inflammation of the periodontium).
  • thermosetting biophotonic compositions can be, in a broad sense, activated by light (e.g., photons) of specific wavelength.
  • a thermosetting biophotonic composition according to various embodiments of the present disclosure contains a block copolymer, with at least one chromophore solubilized in the block copolymer.
  • the chromophore in the thermosetting biophotonic composition may be activated by light, accelerating the dispersion of light energy, which leads to light carrying on a therapeutic effect on its own, and/or to the photochemical activation of other agents contained in the composition (e.g., acceleration in the breakdown process of peroxide (an oxidant or oxidizing agent) when such compound is present in the composition or in contact with the composition, leading to the formation of oxygen radicals, such as singlet oxygen).
  • peroxide an oxidant or oxidizing agent
  • a chromophore When a chromophore absorbs a photon of a certain wavelength, it becomes excited. This is an unstable condition and the molecule tries to return to the ground state, giving away the excess energy. For some chromophores, it is favorable to emit the excess energy as light when returning to the ground state. This process is called fluorescence. The peak wavelength of the emitted fluorescence is shifted towards longer wavelengths compared to the absorption wavelengths due to loss of energy in the conversion process. This is called the Stokes' shift. In the proper environment (e.g., in a biophotonic composition) much of this energy is transferred to the other components of the biophotonic composition or to the treatment site directly.
  • fluorescent light emitted by photoactivated chromophores has therapeutic properties due to its femto-, pico-, or nanosecond emission properties which may be recognized by biological cells and tissues, leading to favourable biomodulation. Furthermore, the emitted fluorescent light has a longer wavelength and hence a deeper penetration into the tissue than the activating light. Irradiating tissue with such a broad range of wavelength, including in some embodiments the activating light which passes through the composition, may have different and complementary effects on the cells and tissues. In other words, chromophores are used in the biophotonic compositions of the present disclosure for therapeutic effect on tissues.
  • the emitted fluorescent light may have an effect that is mechanical in nature by precipitating a disruption in a flow of electrons that results in a destabilization of a bacterial membrane thereby resulting in a loss of structural integrity of the bacterial membrane.
  • This is a distinct application of these photoactive agents and differs from the use of chromophores as simple stains or as catalysts for photo-polymerization.
  • thermosetting biophotonic compositions of the present disclosure may have topical uses.
  • the thermosetting biophotonic compositions are cohesive once they thermoset.
  • the cohesive nature of these thermosetting biophotonic compositions may provide ease of removal from the site of treatment and hence a faster and less messy treatment. Once thermoset, the cohesive nature of these thermosetting biophotonic compositions may also provide a less messy treatment.
  • the thermosetting biophotonic compositions can limit the contact between the chromopore and the tissue.
  • thermosetting compositions of the disclosure are designed to thermoset when they come in contact with target skin tissue.
  • the thermosetting biophotonic composition thermosets at 32deg Celsius or above. In some embodiments, the composition thermosets within 1 minute at 32deg Celsius. In other embodiments, the composition thermosets within 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, 5 seconds, or less than 5 seconds at 32deg Celsius. In other embodiments, the composition thermosets spontaneously on contact with the target tissue.
  • thermosetting biophotonic compositions of the present disclosure including chromophores, block copolymers, and other optional ingredients, are detailed below.
  • Chromophores can be fluorescent compounds (or stains) (also known as “fluorochromes” or “fluorophores”). Other dye groups or dyes (biological and histological dyes, food colorings, carotenoids, and other dyes) can also be used.
  • Photoactivators can be those that are Generally Regarded As Safe (GRAS).
  • GRAS Generally Regarded As Safe
  • photoactivators which are not well tolerated by the skin or other tissues can be included in the thermosetting biophotonic composition of the present disclosure, as in certain embodiments, the photoactivators are dissolved within the block copolymer.
  • thermosetting biophotonic composition of the present disclosure comprises a first chromophore which undergoes partial or complete photobleaching upon application of light.
  • the first chromophore is at least one xanthene dye selected from Eosin Y, Erythrosine B, Fluorescein, Rose Bengal and Phloxin B.
  • a particular chromophore's absorption and/or emission wavelength (or spectrum) corresponds to the wavelengths (or spectrum) measured in a thermosetting biophotonic composition of the present disclosure.
  • thermosetting biophotonic composition disclosed herein may include at least one additional chromophore.
  • Combining chromophores may increase photo-absorption by the combined dye molecules and enhance absorption and photo-biomodulation selectivity. This creates multiple possibilities of generating new photosensitive, and/or selective chromophores mixtures.
  • biophotonic compositions of the disclosure include more than one chromophore. When such multi- chromophore compositions are illuminated with light, energy transfer can occur between the chromophores.
  • resonance energy transfer is a widely prevalent photophysical process through which an excited 'donor' chromophore (also referred to herein as first chromophore) transfers its excitation energy to an 'acceptor' chromophore (also referred to herein as second chromophore).
  • the efficiency and directedness of resonance energy transfer depends on the spectral features of donor and acceptor chromophores.
  • the flow of energy between chromophores is dependent on a spectral overlap reflecting the relative positioning and shapes of the absorption and emission spectra. More specifically, for energy transfer to occur, the emission spectrum of the donor chromophore must overlap with the absorption spectrum of the acceptor chromophore.
  • the donor chromophore should have good abilities to absorb photons and emit photons. Furthermore, the more overlap there is between the donor chromophore's emission spectra and the acceptor chromophore's absorption spectra, the better a donor chromophore can transfer energy to the acceptor chromophore.
  • thermosetting biophotonic composition of the present disclosure further comprises a second chromophore.
  • the first chromophore has an emission spectrum that overlaps at least about 80%, 50%, 40%, 30%, 20% or 10% with an absorption spectrum of the second chromophore. In one embodiment, the first chromophore has an emission spectrum that overlaps at least about 20% with an absorption spectrum of the second chromophore.
  • the first chromophore has an emission spectrum that overlaps at least 1-10%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 50-60%, 55-65% or 60-70% with an absorption spectrum of the second chromophore.
  • % spectral overlap means the % overlap of a donor chromophore's emission wavelength range with an acceptor chromophore's absorption wavelength rage, measured at spectral full width quarter maximum (FWQM).
  • the second chromophore absorbs at a wavelength in the range of the visible spectrum.
  • the second chromophore has an absorption wavelength that is relatively longer than that of the first chromophore within the range of about 50-250, 25-150 or 10-100 nm.
  • the first chromophore can be present in an amount of about 0.001-40% per weight of the biophotonic composition.
  • the second chromophore can be present in an amount of about 0.001-40% per weight of the biophotonic composition.
  • the first chromophore is present in an amount of about 0.001-3%, 0.001- 0.01%, 0.005-0.1%, 0.1-0.5%, 0.5-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%, 10-15%,12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40% per weight of the biophotonic composition.
  • the second chromophore is present in an amount of about 0.001-3%, 0.001-0.01%, 0.005-0.1%, 0.1-0.5%, 0.5-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%, 10- 15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30- 35%, 32.5-37.5%, or 35-40% per weight of the biophotonic composition.
  • the total weight per weight of chromophore or combination of chromophores may be in the amount of about 0.005-1%, 0.05-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%, 10-15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%, 27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40.001% per weight of the biophotonic composition.
  • the concentration of the chromophore to be used can be selected based on the desired intensity and duration of the biophotonic activity from the thermosetting biophotonic composition, and on the desired medical or cosmetic effect. For example, some dyes such as xanthene dyes reach a 'saturation concentration' after which further increases in concentration do not provide substantially higher emitted fluorescence. Further increasing the chromophore concentration above the saturation concentration can reduce the amount of activating light passing through the matrix. Therefore, if more fluorescence is required for a certain application than activating light, a high concentration of chromophore can be used. However, if a balance is required between the emitted fluorescence and the activating light, a concentration close to or lower than the saturation concentration can be chosen.
  • thermosetting biophotonic compositions of the present disclosure include, but are not limited to the following:
  • chlorophyll dyes include but are not limited to chlorophyll a; chlorophyll b; chlorophyllin; bacteriochlorophyll a; bacteriochlorophyll b; bacteriochlorophyll c; bacteriochlorophyll d; protochlorophyll; protochlorophyll a; amphiphilic chlorophyll derivative 1; and amphiphilic chlorophyll derivative 2.
  • Exemplary xanthene dyes include but are not limited to eosin B, eosin B (4',5'- dibromo,2',7'-dinitr- o-fluorescein, dianion); eosin Y (2',4',5',7'-tetrabromo- fluorescein, dianion); eosin (2',4',5',7'-tetrabromo-fluorescein, dianion); eosin (2',4',5',7'-tetrabromo-fluorescein, dianion) methyl ester; eosin (2',4',5',7'-tetrabromo- fluorescein, monoanion) p-isopropylbenzyl ester; eosin derivative (2',7'-dibromo-fluorescein, dianion); eosin derivative (4'
  • Exemplary methylene blue derivatives include but are not limited to I-methyl methylene blue; 1,9-dimethyl methylene blue; methylene blue; methylene violet; bromomethylene violet; 4-iodomethylene violet; 1,9-dimethyl-3-dimethyl-amino-7-diethyl-amino- phenothiazine; and 1,9-dimethyl-3-diethylamino-7-dibutyl-amino-phenot- hiazine.
  • Exemplary azo (or diazo-) dyes include but are not limited to methyl violet, neutral red, para red (pigment red I), amaranth (Azorubine S), Carmoisine (azorubine, food red 3, acid red 14), allura red AC (FD&C 40), tartrazine (FD&C Yellow 5), orange G (acid orange 10), Ponceau 4R (food red 7), methyl red (acid red 2), and murexide-ammonium purpurate.
  • the composition includes Eosin Y as a first chromophore and any one or more of Rose Bengal, Fluorescein, Erythrosine, Phloxine B, chlorophyllin as a second chromophore. It is believed that these combinations have a synergistic effect as they can transfer energy to one another when activated due in part to overlaps or close proximity of their absorption and emission spectra. This transferred energy is then emitted as fluorescence or leads to production of reactive oxygen species. This absorbed and re-emitted light is thought to be transmitted throughout the composition, and also to be transmitted into the site of treatment.
  • the composition includes the following synergistic combinations: Eosin Y and Fluorescein; Fluorescein and Rose Bengal; Erythrosine in combination with Eosin Y, Rose Bengal or Fluorescein; Phloxine B in combination with one or more of Eosin Y, Rose Bengal, Fluorescein and Erythrosine.
  • synergistic chromophore combinations are also possible.
  • thermosetting biophotonic composition By means of synergistic effects of the chromophore combinations in the thermosetting biophotonic composition, chromophores which cannot normally be activated by an activating light (such as a blue light from an LED), can be activated through energy transfer from chromophores which are activated by the activating light. In this way, the different properties of photoactivated chromophores can be harnessed and tailored according to the cosmetic or the medical therapy required.
  • an activating light such as a blue light from an LED
  • Rose Bengal can generate a high yield of singlet oxygen when activated in the presence of molecular oxygen, however it has a low quantum yield in terms of emitted fluorescent light.
  • Rose Bengal has a peak absorption around 540 nm and so can be activated by green light.
  • Eosin Y has a high quantum yield and can be activated by blue light.
  • the blue light photoactivates Eosin Y, which transfers some of its energy to Rose Bengal as well as emitting some energy as fluorescence.
  • the chromophore or chromophores are selected such that their emitted fluorescent light, on photoactivation, is within one or more of the green, yellow, orange, red and infrared portions of the electromagnetic spectrum, for example having a peak wavelength within the range of about 490 nm to about 800 nm.
  • the emitted fluorescent light has a power density of between 0.005 to about 10 mW/cm 2 , about 0.5 to about 5 mW/cm 2 .
  • thermosetting biophotonic composition of the present disclosure comprises a block copolymer.
  • the block copolymer is present in an amount of more than 20% weight per volume of the total composition. In some embodiments, the block copolymer is present in an amount of at least 21%, 22%, 23%, 24% or 25%. In some embodiments, the block copolymer is present in an amount of21%, 22%, 23%, 24% or 25%.
  • block copolymer refers to a copolymer comprised of 2 or more blocks (or segments) of different homopolymers.
  • the block copolymer in the thermosetting biophotonic composition of the invention comprises at least one sequence of polyethylene glycol-propylene glycol (PEG-PPG), polyethylene glycol-poly(lactic acid) (PEG-PLA) or polyethylene glycol-poly( ⁇ -caprolacone) (PEG-PCL).
  • PEG-PPG polyethylene glycol-propylene glycol
  • PEG-PLA polyethylene glycol-poly(lactic acid)
  • PEG-PCL polyethylene glycol-poly( ⁇ -caprolacone)
  • a polymer is "biocompatible" in that the polymer and degradation products thereof are substantially non-toxic to cells or organisms, including non- carcinogenic and non-immunogenic, and are cleared or otherwise degraded in a biological system, such as an organism (patient) without substantial toxic effect.
  • the block copolymer is from a group of tri-block copolymers designated Poloxamers.
  • Poloxamers are A-B-A block copolymers in which the A segment is a hydrophilic polyethylene glycol (PEG) homopolymer and the B segment is hydrophobic polypropylene glycol (PPG) homopolymer. Poloxamers and use in pharmaceutical compositions are disclosed in Van Hemelrijk& al. (International Journal of Pharmmaceutics, 2011, vol.
  • PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular weight.
  • PPG is also known as polypropylene oxide (PPO), depending on its molecular weight.
  • Poloxamers are commercially available from BASF Corporation. Poloxamers produce reverse thermal gelatin compositions, i.e., with the characteristic that their viscosity increases with increasing temperature up to a point from which viscosity again decreases. Depending on the relative size of the blocks the copolymer can be a solid, liquid or paste.
  • the poloxamer is Pluronic® F127 (also known as Poloxamer 407).
  • thermosetting biophotonic composition of the disclosure comprises Pluronic® F127 in the amount of more than 20% weight per volume of the composition.
  • the pluronic is present in the amount of at least 21%, 22%, 23%, 24%, or 25%.
  • Other poloxamers can also be used.
  • the PEG blocks contribute hydrophilicity to the polymer, increasing the length of the PEG blocks or the total amount of PEG in the polymer will tend to make the polymer more hydrophilic.
  • the desired overall hydrophilicity, and the nature and chemical functional groups of any drug or therapeutic agent that may be included in a formulation of the polymer a skilled person can readily adjust the length (or MW) of the PEG blocks used and/or the total amount of PEG incorporated into the polymer, in order to obtain a polymer having the desired physical and chemical characteristics.
  • the total amount of PEG in the polymer may be about 80 wt % or less, 75 wt % or less, 70 wt % or less, 65 wt % or less, about 60 wt % or less, about 55 wt % or less, or about 50 wt % or less.
  • the total amount of PEG is about 55 wt %, 56 wt %, 57 wt %, 58 wt %, 59 wt %, 60 wt %, 61 wt %, 62 wt %, 63 wt %, 64 wt %, 65 wt %, 66 wt %, 67 wt %, 68 wt %, 69 wt %, or about 70 wt %.
  • a weight percentage of a particular component of the polymer means that the total weight of the polymer is made up of the specified percentage of monomers of that component.
  • 65 wt % PEG means that 65% of the weight of the polymer is made up of PEG monomers, which monomers are linked into blocks of varying lengths, which blocks are distributed along the length of polymer, including in a random distribution.
  • surfactants can enhance the fluorescence of the chromophore.
  • complimentary surfactant and chromophore combinations can be tested and selected based on non-electrically repelling combinations.
  • a negatively charged chromophore can be used with an ionic or non-ionic surfactant, and vice versa.
  • the block copolymer may also be mixed with thickening agents or stabilizers such as gelatin and/or modified celluloses such as hydroxyethyl cellulose (HEC) and carboxymethyl cellulose (CMD), and/or polysaccharides such as xanthan gum, guar gum, and/or starches and/or any other thickening agent.
  • the stabilizer or thickening agent may comprise gelatin.
  • the surfactant phase may comprise about 0-5 wt%, about 5-25 wt%, about 0-15 wt%, or about 10-20 wt% gelatin.
  • Thickening agents and/or stabilizers may be selected according to effects they will have on the optical transparency of the biophotonic membrane or the stabilizing effect on the block copolymer.
  • the thermosetting biophotonic composition should be able to transmit sufficient light to activate the at least one chromophore.
  • thermosetting biophotonic composition of the present disclosure may optionally comprise one or more additional components, such as oxygen-rich compounds as a source of oxygen radicals ("oxidants").
  • oxygen-rich compounds are oxidants that contain the peroxy group (R-O-O-R), which is a chainlike structure containing two oxygen atoms, each of which is bonded to the other and a radical or some element.
  • thermosetting biophotonic composition of the present disclosure potentially a bactericidal composition.
  • Antimicrobials kill microbes or inhibit their growth or accumulation, and are optionally included in the thermosetting biophotonic composition of the present disclosure.
  • Suitable antimicrobials for use in the methods and compositions of the present disclosure include, but not limited to, hydrogen peroxide, urea hydrogen peroxide, benzoyl peroxide, phenolic and chlorinated phenolic and chlorinated phenolic compounds, resorcinol and its derivatives, bisphenolic compounds, benzoic esters (parabens), halogenated carbonilides, polymeric antimicrobial agents, thazolines, trichloromethylthioimides, natural antimicrobial agents (also referred to as "natural essential oils”), metal salts, and broad-spectrum antibiotics.
  • Hydrogen peroxide (H 2 O 2 ) is a powerful oxidizing agent, and breaks down into water and oxygen and does not form any persistent, toxic residual compound.
  • a suitable range of concentration over which hydrogen peroxide can be used in the biophotonic composition is from about 0.1% to about 3%, about 0.1 to 1.5%, about 0.1% to about 1%, about 1%, less than about 1%.
  • Urea peroxide also known as carbamide peroxide or percarbamide
  • Urea peroxide is soluble in water and contains approximately 35% hydrogen peroxide.
  • a suitable range of concentration over which urea peroxide can be used in the biophotonic composition of the present disclosure is less than about 0.25 %, or less than about 0.3%, from 0.001 to 0.25%, or from about 0.3% to about 5%.
  • Urea peroxide breaks down to urea and hydrogen peroxide in a slow-release fashion that can be accelerated with heat or photochemical reactions.
  • Benzoyl peroxide consists of two benzoyl groups (benzoic acid with the H of the carboxylic acid removed) joined by a peroxide group. It is found in treatments for acne, in concentrations varying from 2.5% to 10%. The released peroxide groups are effective at killing bacteria. Benzoyl peroxide also promotes skin turnover and clearing of pores, which further contributes to decreasing bacterial counts and reduce acne. Benzoyl peroxide breaks down to benzoic acid and oxygen upon contact with skin, neither of which is toxic. A suitable range of concentration over which benzoyl peroxide can be used in the thermosetting biophotonic composition is from about 2.5% to about 5%.
  • phenolic and chlorinated phenolic antimicrobial agents that can be used in the disclosure include, but are not limited to: phenol; 2-methyl phenol; 3-methyl phenol; 4-methyl phenol; 4-ethyl phenol; 2,4-dimethyl phenol; 2,5-dimethyl phenol; 3,4-dimethyl phenol; 2,6-dimethyl phenol; 4-n-propyl phenol; 4-n-butyl phenol; 4-n-amyl phenol; 4-tert-amyl phenol; 4-n-hexyl phenol; 4-n-heptyl phenol; mono- and poly-alkyl and aromatic halophenols; p-chlorophenyl; methyl p-chlorophenol; ethyl p-chlorophenol; n-propyl p-chlorophenol; n-butyl p-chlorophenol; n-amyl p-chlorophenol; sec-amyl p-chlorophenol; n
  • Resorcinol and its derivatives can also be used as antimicrobial agents.
  • Specific resorcinol derivatives include, but are not limited to: methyl resorcinol; ethyl resorcinol; n-propyl resorcinol; n-butyl resorcinol; n-amyl resorcinol; n-hexyl resorcinol; n-heptyl resorcinol; n-octyl resorcinol; n-nonyl resorcinol; phenyl resorcinol; benzyl resorcinol; phenylethyl resorcinol; phenylpropyl resorcinol; p-chlorobenzyl resorcinol; 5-chloro-2,4-dihydroxydiphenyl methane; 4'-chloro-2,4-dihydroxydiphen
  • bisphenolic antimicrobial agents that can be used in the disclosure include, but are not limited to: 2,2'-methylene bis-(4-chlorophenol); 2,4,4'trichloro-2'-hydroxydiphenyl ether, which is sold by Ciba Geigy, Florham Park, N.J. under the tradename Triclosan®; 2,2'-methylene bis-(3,4,6-trichlorophenol); 2,2'-methylene bis-(4-chloro-6-bromophenol); bis-(2-hydroxy-3,5-dichlorop- henyl) sulphide; and bis-(2-hydroxy-5-chlorobenzyl)sulphide.
  • benzoie esters that can be used in the disclosure include, but are not limited to: methylparaben; propylparaben; butylparaben; ethylparaben; isopropylparaben; isobutylparaben; benzylparaben; sodium methylparaben; and sodium propylparaben.
  • halogenated carbanilides that can be used in the disclosure include, but are not limited to: 3,4,4'-trichlorocarbanilides, such as 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea sold under the tradename Triclocarban® by Ciba-Geigy, Florham Park, N.J.; 3-trifluoromethyl-4,4'-dichlorocarbanilide; and 3,3',4-trichlorocarbanilide.
  • 3,4,4'-trichlorocarbanilides such as 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea sold under the tradename Triclocarban® by Ciba-Geigy, Florham Park, N.J.
  • Triclocarban® 3-trifluoromethyl-4,4'-dichlorocarbanilide
  • 3,3',4-trichlorocarbanilide 3,3',4-trichlor
  • polymeric antimicrobial agents that can be used in the disclosure include, but are not limited to: polyhexamethylene biguanide hydrochloride; and poly(iminoimidocarbonyl iminoimidocarbonyl iminohexamethylene hydrochloride), which is sold under the tradename Vantocil® IB.
  • thazolines that can be used in the disclosure include, but are not limited to that sold under the tradename Micro-Check®; and 2-n-octyl-4-isothiazolin-3-one, which is sold under the tradename Vinyzene® IT-3000 DIDP.
  • trichloromethylthioimides that can be used in the disclosure include, but are not limited to: N-(trichloromethylthio)phthalimide, which is sold under the tradename Fungitrol®; and N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide, which is sold under the tradename Vancide®.
  • Specific natural antimicrobial agents that can be used in the disclosure include, but are not limited to, oils of: anise; lemon; orange; rosemary; wintergreen; thyme; lavender; cloves; hops; tea tree; citronella; wheat; barley; lemongrass; cedar leaf; cedarwood; cinnamon; fleagrass; geranium; sandalwood; violet; cranberry; eucalyptus; vervain; peppermint; gum benzoin; basil; fennel; fir; balsam; menthol; ocmea origanuin; hydastis; carradensis; Berberidaceac daceae; Ratanhiae longa; and Curcuma longa.
  • Also included in this class of natural antimicrobial agents are the key chemical components of the plant oils which have been found to provide antimicrobial benefit. These chemicals include, but are not limited to: anethol; catechole; camphene; thymol; eugenol; eucalyptol; ferulic acid; farnesol; hinokitiol; tropolone; limonene; menthol; methyl salicylate; carvacol; terpineol; verbenone; berberine; ratanhiae extract; caryophellene oxide; citronellic acid; curcumin; nerolidol; and geraniol.
  • anethol catechole; camphene; thymol; eugenol; eucalyptol; ferulic acid; farnesol; hinokitiol; tropolone; limonene; menthol; methyl salicylate; carvacol; terpineo
  • Specific metal salts that can be used in the disclosure include, but are not limited to, salts of metals in groups 3a-5a, 3b-7b, and 8 of the periodic table.
  • Specific examples of metal salts include, but are not limited to, salts of: aluminum; zirconium; zinc; silver; gold; copper; lanthanum; tin; mercury; bismuth; selenium; strontium; scandium; yttrium; cerium; praseodymiun; neodymium; promethum; samarium; europium; gadolinium; terbium; dysprosium; holmium; erbium; thalium; ytterbium; lutetium; and mixtures thereof.
  • An example of the metal-ion based antimicrobial agent is sold under the tradename HealthShield®, and is manufactured by HealthShield Technology, Wakefield, Mass.
  • Specific broad-spectrum antimicrobial agents that can be used in the disclosure include, but are not limited to, those that are recited in other categories of antimicrobial agents herein.
  • Additional antimicrobial agents that can be used in the methods of the disclosure include, but are not limited to: pyrithiones, and in particular pyrithione-including zinc complexes such as that sold under the tradename Octopirox®; dimethyidimethylol hydantoin, which is sold under the tradename Glydant®; methylchloroisothiazolinone/methylisothiazolinone, which is sold under the tradename Kathon CG®; sodium sulfite; sodium bisulfite; imidazolidinyl urea, which is sold under the tradename Germall 115®; diazolidinyl urea, which is sold under the tradename Germall 11®; benzyl alcohol v2-bromo-2-nitropropane-1,3-diol, which is sold under the tradename Bronopol®; formalin or formaldehyde; iodopropenyl butylcarbamate, which is sold under the tradename
  • biophotonic compositions of the present disclosure are substantially transparent or translucent.
  • the % transmittance of the biophotonic composition can be measured in the range of wavelengths from 250 nm to 800 nm using, for example, a Perkin-Elmer Lambda 9500 series UV-visible spectrophotometer. In some embodiments, transmittance within the visible range is measured and averaged. In some other embodiments, transmittance of the thermosetting biophotonic composition is measured with the chromophore omitted. As transmittance is dependent upon thickness, the thickness of each sample can be measured with calipers prior to loading in the spectrophotometer.
  • transmittance measurements are usually normalized to 1 cm.
  • the biophotonic composition has a transmittance that is more than about 20%, 30%, 40%, 50%, 60%, 70%, or 75% within the visible range. In some embodiments, the transmittance exceeds 40%, 41%, 42%, 43%, 44%, or 45% within the visible range. In some embodiments, the composition has a light transmittance of about 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80- 100%, 85-100%, 90-100%, or 95-100%.
  • thermosetting biophotonic composition of the present disclosure may have cosmetic and/or medical benefits. They can be used to promote skin rejuvenation and skin conditioning, promote the treatment of a skin disorder such as acne, eczema, dermatitis or psoriasis, promote tissue repair, promote wound healing including periodontal pockets, prevent or treat scarring, prevent or treat bacterial, fungal or viral infections. They can be used to treat acute inflammation. Acute inflammation can present itself as pain, heat, redness, swelling and loss of function. It includes those seen in allergic reactions such as insect bites e.g.; mosquito, bees, wasps, poison ivy, or post-ablative treatment.
  • any source of actinic light can be used. Any type of halogen, LED or plasma arc lamp, or laser may be suitable.
  • the primary characteristic of suitable sources of actinic light will be that they emit light in a wavelength (or wavelengths) appropriate for activating the one or more photoactivators present in the composition.
  • an argon laser is used.
  • a potassium-titanyl phosphate (KTP) laser e.g. a GreenLightTM laser
  • a LED lamp such as a photocuring device is the source of the actinic light.
  • the source of the actinic light is a source of light having a wavelength between about 200 to 800 nm.
  • the source of the actinic light is a source of visible light having a wavelength between about 400 and 600 nm. In another embodiment, the source of the actinic light is a source of visible light having a wavelength between about 400 and 800 nm. In another embodiment, the source of the actinic light is a source of visible light having a wavelength between about 400 and 700 nm. In yet another embodiment, the source of the actinic light is blue light. In yet another embodiment, the source of the actinic light is red light. In yet another embodiment, the source of the actinic light is green light. Furthermore, the source of actinic light should have a suitable power density.
  • Suitable power density for non-collimated light sources are in the range from about 0.1 mW/cm 2 to about 200 mW/cm 2 •
  • Suitable power density for laser light sources are in the range from about 0.5 mW/cm 2 to about 0.8 mW/cm 2 .
  • the light has an energy at the subject's skin surface of between about 0.1 mW/cm 2 and about 500 mW/cm 2 or 0.1-300 mW/cm 2 , or 0.1-200 mW/cm 2 , wherein the energy applied depends at least on the condition being treated, the wavelength of the light, the distance of the skin from the light source and the thickness of the biophotonic composition applied to the target skin or wound.
  • the light at the subject's skin is between about 1-40 mW/cm 2 , or 20-60 mW/cm 2 , or 40-80 mW/cm 2 , or 60-100 mW/cm 2 , or 80-120 mW/cm 2 , or 100-140 mW/cm 2 , or 30-180 mW/cm 2 , or 120-160 mW/cm 2 , or 140-180 mW/cm 2 , or 160-200 mW/cm 2 , or 110-240 mW/cm 2 , or 110-150 mW/cm 2 , or 190-240 mW/cm 2 .
  • the activation of the chromophore(s) within the biophotonic composition may take place almost immediately on illumination (femto- or pico seconds). A prolonged exposure period may be beneficial to exploit the synergistic effects of the absorbed, reflected and reemitted light of the biophotonic composition of the present disclosure and its interaction with the tissue being treated.
  • the time of exposure of the tissue or skin or biophotonic composition to actinic light may be a period between .01 minutes and 90 minutes. In another embodiment, the time of exposure of the tissue or skin or biophotonic composition to actinic light is a period between 1 minute and 5 minutes. In some other embodiments, the biophotonic composition is illuminated for a period between 1 minute and 3 minutes.
  • light is applied for a period of 1-30 seconds, 15-45 seconds, 30-60 seconds, 0.75-1.5 minutes, 1-2 minutes, 1.5-2.5 minutes, 2-3 minutes, 2.5-3.5 minutes, 3-4 minutes, 3.5-4.5 minutes, 4-5 minutes, 5-10 minutes, 10-15 minutes, 15-20 minutes, or 20-30 minutes.
  • the treatment time may range up to about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes or about 30 minutes. It will be appreciated that the treatment time can be adjusted in order to maintain a dosage by adjusting the rate of fluence delivered to a treatment area.
  • the delivered fluence may be about 4 to about 60 J/cm 2 , about 10 to about 60 J/cm 2 , 4 to about 90 J/cm 2 , about 10 to about 90 J/cm 2 about 10 to about 50 J/cm 2 about 10 to about 40 J/cm 2 , about 10 to about 30 J/cm 2 , about 20 to about 40 J/cm 2 , about 15 J/cm 2 to 25 J/cm 2 , or about 10 to about 20 J/cm 2 .
  • thermosetting biophotonic composition may be reilluminated at certain intervals.
  • the source of actinic light is in continuous motion over the treated area for the appropriate time of exposure.
  • the thermosetting biophotonic composition may be illuminated until the chromophore is at least partially photobleached or fully photobleached.
  • the chromophore(s) can be photoexcited by ambient light including from the sun and overhead lighting.
  • the chromophore(s) can be photoactivated by light in the visible range of the electromagnetic spectrum.
  • the light can be emitted by any light source such as sunlight, light bulb, an LED device, electronic display screens such as on a television, computer, telephone, mobile device, flashlights on mobile devices.
  • any source of light can be used.
  • Ambient light can include overhead lighting such as LED bulbs, fluorescent bulbs etc, and indirect sunlight.
  • thermosetting biophotonic composition may be removed from the skin following application of light. Otherwise, the thermosetting biophotonic composition is left on the tissue for an extended period of time and reactivated with direct or ambient light at appropriate times to treat the condition.
  • thermosetting biophotonic composition can be applied to the tissue, such as on the face, once, twice, three times, four times, five times or six times a week, daily, or at any other frequency.
  • the total treatment time can be one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or any other length of time deemed appropriate.
  • the total tissue area to be treated may be split into separate areas (cheeks, forehead), and each area treated separately.
  • the thermosetting biophotonic composition may be applied topically to a first portion of the skin, and that portion illuminated with light, and the composition then removed. Then the biophotonic composition is applied to a second portion of the skin, illuminated and removed. Finally, the biophotonic composition is applied to a third portion, illuminated and removed.
  • thermosetting biophotonic composition can be used following wound closure to optimize scar revision.
  • the thermosetting biophotonic composition may be applied at regular intervals such as once a week, or at an interval deemed appropriate by the physician.
  • thermosetting biophotonic composition can be used following acne treatment to maintain the condition of the treated skin.
  • the composition may be applied at regular intervals such as once a week, or at an interval deemed appropriate by the physician.
  • thermosetting biophotonic composition can be used following ablative skin rejuvenation treatment to maintain the condition of the treated skin.
  • the composition may be applied at regular intervals such as once a week, or at an interval deemed appropriate by the physician.
  • thermosetting biophotonic composition can be used to treat eczema or psoriasis.
  • the composition may be applied at regular intervals such as once a week, or at an interval deemed appropriate by the physician. It may be less painful to the patient to spray the composition onto the affected area.
  • Additional components may optionally be included in the thermosetting biophotonic composition or used in combination with the compositions.
  • additional components include, but are not limited to, healing factors, antimicrobials, oxygen-rich agents, wrinkle fillers such as botox, hyaluronic acid and polylactic acid, fungal, anti-bacterial, anti-viral agents and/or agents that promote collagen synthesis.
  • healing factors comprise compounds that promote or enhance the healing or regenerative process of the tissues on the application site.
  • thermosetting biophotonic composition of the present disclosure there may be an increase of the absorption of molecules of such additional components at the treatment site by the skin or the mucosa.
  • an augmentation in the blood flow at the site of treatment can observed for a period of time.
  • An increase in the lymphatic drainage and a possible change in the osmotic equilibrium due to the dynamic interaction of the free radical cascades can be enhanced or even fortified with the inclusion of healing factors.
  • Healing factors may also modulate the biophotonic output from the biophotonic composition such as photobleaching time and profile, or modulate leaching of certain ingredients within the composition. Suitable healing factors include, but are not limited to glucosamines, allantoins, saffron, agents that promote collagen synthesis, anti-fungal, anti-bacterial, anti-viral agents and wound healing factors such as growth factors.
  • thermosetting biophotonic compositions of the present disclosure may be useful in promoting skin rejuvenation or improving skin condition and appearance.
  • the dermis is the second layer of skin, containing the structural elements of the skin, the connective tissue.
  • connective tissue There are various types of connective tissue with different functions. Elastin fibers give the skin its elasticity, and collagen gives the skin its strength.
  • the junction between the dermis and the epidermis is an important structure.
  • the dermal-epidermal junction interlocks forming finger-like epidermal ridges.
  • the cells of the epidermis receive their nutrients from the blood vessels in the dermis.
  • the epidermal ridges increase the surface area of the epidermis that is exposed to these blood vessels and the needed nutrients.
  • the aging of skin comes with significant physiological changes to the skin.
  • the generation of new skin cells slows down, and the epidermal ridges of the dermal-epidermal junction flatten out. While the number of elastin fibers increases, their structure and coherence decreases. Also the amount of collagen and the thickness of the dermis decrease with the ageing of the skin.
  • Collagen is a major component of the skin's extracellular matrix, providing a structural framework. During the aging process, the decrease of collagen synthesis and insolubilization of collagen fibers contribute to a thinning of the dermis and loss of the skin's biomechanical properties.
  • the physiological changes to the skin result in noticeable aging symptoms often referred to as chronological-, intrinsic- and photo-aging.
  • the skin becomes drier, roughness and scaling increase, the appearance becomes duller, and most obviously fine lines and wrinkles appear.
  • Other symptoms or signs of skin aging include, but are not limited to, thinning and transparent skin, loss of underlying fat (leading to hollowed cheeks and eye sockets as well as noticeable loss of firmness on the hands and neck), bone loss (such that bones shrink away from the skin due to bone loss, which causes sagging skin), dry skin (which might itch), inability to sweat sufficiently to cool the skin, unwanted facial hair, freckles, age spots, spider veins, rough and leathery skin, fine wrinkles that disappear when stretched, loose skin, a blotchy complexion.
  • the dermal-epidermal junction is a basement membrane that separates the keratinocytes in the epidermis from the extracellular matrix, which lies below in the dermis.
  • This membrane consists of two layers: the basal lamina in contact with the keratinocytes, and the underlying reticular lamina in contact with the extracellular matrix.
  • the basal lamina is rich in collagen type IV and laminin, molecules that play a role in providing a structural network and bioadhesive properties for cell attachment.
  • Laminin is a glycoprotein that only exists in basement membranes. It is composed of three polypeptide chains (alpha, beta and gamma) arranged in the shape of an asymmetric cross and held together by disulfide bonds. The three chains exist as different subtypes which result in twelve different isoforms for laminin, including Laminin-1 and Laminin-5.
  • the dermis is anchored to hemidesmosomes, specific junction points located on the keratinocytes, which consist of a-integrins and other proteins, at the basal membrane keratinocytes by type VII collagen fibrils.
  • Laminins, and particularly Laminin-5 constitute the real anchor point between hemidesmosomal transmembrane proteins in basal keratinocytes and type VII collagen.
  • Laminin-5 synthesis and type VII collagen expression have been proven to decrease in aged skin. This causes a loss of contact between dermis and epidermis, and results in the skin losing elasticity and becoming saggy.
  • Expression wrinkles result from a loss of resilience, particularly in the dermis, because of which the skin is no longer able to resume its original state when facial muscles which produce facial expressions.
  • thermosetting biophotonic composition may be used in conjunction with collagen promoting agents.
  • Agents that promote collagen synthesis include amino acids, peptides, proteins, lipids, small chemical molecules, natural products and extracts from natural products.
  • vitamin C examples include an ascorbic acid derivative such as L-ascorbic acid or sodium L-ascorbate, an ascorbic acid preparation obtained by coating ascorbic acid with an emulsifier or the like, and a mixture containing two or more of those vitamin Cs at an arbitrary rate.
  • natural products containing vitamin C such as acerola or lemon may also be used.
  • iron preparation examples include: an inorganic iron such as ferrous sulfate, sodium ferrous citrate, or ferric pyrophosphate; an organic iron such as heme iron, ferritin iron, or lactoferrin iron; and a mixture containing two or more of those irons at an arbitrary rate.
  • inorganic iron such as ferrous sulfate, sodium ferrous citrate, or ferric pyrophosphate
  • organic iron such as heme iron, ferritin iron, or lactoferrin iron
  • natural products containing iron such as spinach or liver may also be used.
  • examples of the collagen include: an extract obtained by treating bone, skin, or the like of a mammal such as bovine or swine with an acid or alkaline; a peptide obtained by hydrolyzing the extract with a protease such as pepsin, trypsin, or chymotrypsin; and a mixture containing two or more of those collagens at an arbitrary rate.
  • Collagens extracted from plant sources may also be used.
  • thermosetting biophotonic compositions of the present disclosure may be used to treat skin disorders that include, but are not limited to, erythema, telangiectasia, actinic telangiectasia, basal cell carcinoma, contact dermatitis, dermatofibrosarcoma protuberans, genital warts, hidradenitis suppurativa, melanoma, merkel cell carcinoma, nummular dermatitis, molloscum contagiosum, psoriasis, psoriatic arthritis, rosacea, scabies, scalp psoriasis, sebaceous carcinoma, squamous cell carcinoma, seborrheic dermatitis, seborrheic keratosis, shingles, tinea versicolor, warts, skin cancer, pemphigus, sunburn, dermatitis, eczema, rashes, impetigo, lichen simplex chronicus, rhinophyma,
  • Dermatitis includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, and statis dermatitis.
  • Skin cancers include melanoma, basal cell carcinoma, and squamous cell carcinoma.
  • thermosetting biophotonic compositions of the present disclosure may be used to treat acne.
  • acne means a disorder of the skin caused by inflammation of skin glands or hair follicles.
  • the thermosetting biophotonic compositions and methods of the disclosure can be used to treat acne at early pre- emergent stages or later stages where lesions from acne are visible. Mild, moderate and severe acne can be treated with embodiments of the biophotonic compositions .
  • Early pre-emergent stages of acne usually begin with an excessive secretion of sebum or dermal oil from the sebaceous glands located in the pilosebaceous apparatus. Sebum reaches the skin surface through the duct of the hair follicle.
  • thermosetting biophotonic compositions of the present disclosure can be used to treat one or more of skin irritation, pitting, development of scars, comedones, inflammatory papules, cysts, hyperkeratinazation, and thickening and hardening of sebum associated with acne.
  • Some skin disorders present various symptoms including redness, flushing, burning, scaling, pimples, papules, pustules, comedones, macules, nodules, vesicles, blisters, telangiectasia, spider veins, sores, surface irritations or pain, itching, inflammation, red, purple, or blue patches or discolorations, moles, and/or tumors.
  • thermosetting biophotonic compositions of the present disclosure may be used to treat various types of acne.
  • Some types of acne include, for example, acne vulgaris, cystic acne, acne atrophica, bromide acne, chlorine acne, acne conglobata, acne cosmetica, acne detergicans, epidemic acne, acne estivalis, acne fulminans, halogen acne, acne indurata, iodide acne, acne keloid, acne mechanica, acne papulosa, pomade acne, premenstral acne, acne pustulosa, acne scorbutica, acne scrofulosorum, acne urticata, acne varioliformis, acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne, and nodulocystic acne.
  • thermosetting biophotonic composition of the present disclosure may be used in conjunction with systemic or topical antibiotic treatment.
  • antibiotics used to treat acne include tetracycline, erythromycin, minocycline, doxycycline, which may also be used with the compositions of the present disclosure.
  • the use of the thermosetting biophotonic composition can reduce the time needed for the antibiotic treatment or reduce the dosage.
  • thermosetting biophotonic compositions of the present disclosure may be used to treat wounds, promote wound healing.
  • Wounds that may be treated by the biophotonic compositions and methods of the present disclosure include, for example, injuries to the skin and subcutaneous tissue initiated in different ways (e.g., pressure ulcers from extended bed rest, wounds induced by trauma or surgery, bums, ulcers linked to diabetes or venous insufficiency, wounds induced by conditions such as periodontitis) and with varying characteristics.
  • thermosetting biophotonic compositions may be used for treating and/or promoting the healing of, for example, burns, incisions, excisions, lesions, lacerations, abrasions, puncture or penetrating wounds, surgical wounds, contusions, hematomas, crushing injuries, amputations, sores and ulcers.
  • thermosetting biophotonic composition of the present disclosure may be used to treat and/or promote the healing of chronic cutaneous ulcers or wounds, which are wounds that have failed to proceed through an orderly and timely series of events to produce a durable structural, functional, and cosmetic closure.
  • chronic wounds can be classified into three categories based on their etiology: pressure ulcers, neuropathic (diabetic foot) ulcers and vascular (venous or arterial) ulcers.
  • thermosetting biophotonic compositions may be used for treating and/or promoting healing of a diabetic ulcer.
  • Diabetic patients are prone to foot and other ulcerations due to both neurologic and vascular complications.
  • Peripheral neuropathy can cause altered or complete loss of sensation in the foot and/or leg.
  • Diabetic patients with advanced neuropathy lose all ability for sharp- dull discrimination. Any cuts or trauma to the foot may go completely unnoticed for days or weeks in a patient with neuropathy.
  • a patient with advanced neuropathy loses the ability to sense a sustained pressure insult, as a result, tissue ischemia and necrosis may occur leading to for example, plantar ulcerations.
  • Microvascular disease is one of the significant complications for diabetics which may also lead to ulcerations.
  • the thermosetting biophotonic compositions may be used for treating a chronic wound, where the chronic wound is characterized by diabetic foot ulcers and/or ulcerations due to neurologic and/or vascular complications of diabetes.
  • the present thermosetting biophotonic compositions may be used for treating and/or promoting healing of a pressure ulcer.
  • Pressure ulcers include bed sores, decubitus ulcers and ischial tuberosity ulcers and can cause considerable pain and discomfort to a patient.
  • a pressure ulcer can occur as a result of a prolonged pressure applied to the skin.
  • pressure can be exerted on the skin of a patient due to the weight or mass of an individual.
  • a pressure ulcer can develop when blood supply to an area of the skin is obstructed or cut off for more than two or three hours. The affected skin area can turn red, become painful and necrotic. If untreated, the skin can break open and become infected.
  • a pressure ulcer is therefore a skin ulcer that occurs in an area of the skin that is under pressure from e.g. lying in bed, sitting in a wheelchair, and/or wearing a cast for a prolonged period of time.
  • Pressure ulcers can occur when a person is bedridden, unconscious, unable to sense pain, or immobile.
  • Pressure ulcers often occur in boney prominences of the body such as the buttocks area (on the sacrum or iliac crest), or on the heels of foot.
  • inflammatory phase which typically occurs from the moment a wound occurs until the first two to five days, platelets aggregate to deposit granules, promoting the deposit of fibrin and stimulating the release of growth factors.
  • Leukocytes migrate to the wound site and begin to digest and transport debris away from the wound.
  • monocytes are also converted to macrophages, which release growth factors for stimulating angiogenesis and the production of fibroblasts.
  • Fibroblasts which are key cell types in this phase, proliferate and synthesize collagen to fill the wound and provide a strong matrix on which epithelial cells grow. As fibroblasts produce collagen, vascularization extends from nearby vessels, resulting in granulation tissue. Granulation tissue typically grows from the base of the wound. Epithelialization involves the migration of epithelial cells from the wound surfaces to seal the wound. Epithelial cells are driven by the need to contact cells of like type and are guided by a network of fibrin strands that function as a grid over which these cells migrate. Contractile cells called myofibroblasts appear in wounds, and aid in wound closure. These cells exhibit collagen synthesis and contractility, and are common in granulating wounds.
  • the final phase of wound healing which can take place from three weeks up to several years, collagen in the scar undergoes repeated degradation and re-synthesis. During this phase, the tensile strength of the newly formed skin increases.
  • Scarring is a consequence of the healing process in most adult animal and human tissues.
  • Scar tissue is not identical to the tissue which it replaces, as it is usually of inferior functional quality.
  • the types of scars include, but are not limited to, atrophic, hypertrophic and keloidal scars, as well as scar contractures.
  • Atrophic scars are flat and depressed below the surrounding skin as a valley or hole.
  • Hypertrophic scars are elevated scars that remain within the boundaries of the original lesion, and often contain excessive collagen arranged in an abnormal pattern.
  • Keloidal scars are elevated scars that spread beyond the margins of the original wound and invade the surrounding normal skin in a way that is site specific, and often contain whorls of collagen arranged in an abnormal fashion.
  • normal skin consists of collagen fibers arranged in a basket-weave pattern, which contributes to both the strength and elasticity of the dermis.
  • an approach is needed that not only stimulates collagen production, but also does so in a way that reduces scar formation.
  • thermosetting biophotonic compositions of the present disclosure promote the wound healing by promoting the formation of substantially uniform epithelialization; promoting collagen synthesis; promoting controlled contraction; and/or by reducing the formation of scar tissue.
  • the thermosetting biophotonic compositions of the present disclosure may promote wound healing by promoting the formation of substantially uniform epithelialization.
  • the thermosetting biophotonic compositions of the present disclosure may promote collagen synthesis.
  • the thermosetting biophotonic compositions of the present disclosure may promote controlled contraction.
  • the thermosetting biophotonic compositions and methods of the present disclosure may promote wound healing, for example, by reducing the formation of scar tissue.
  • thermosetting biophotonic compositions of the present disclosure may also be used in combination with negative pressure assisted wound closure devices and systems.
  • thermosetting biophotonic compositions may be kept in place for up to one, two or 3 weeks, and illuminated with light which may include ambient light at various intervals.
  • the composition may be covered up in between exposure to light with an opaque composition or left exposed to light.
  • the present disclosure also provides kits for preparing a thermosetting biophotonic composition and/or providing any of the components required for forming thermosetting biophotonic compositions of the present disclosure.
  • the kit may include containers comprising the components or compositions that can be used to make the thermosetting biophotonic compositions of the present disclosure.
  • the kit may include a thermosetting biophotonic composition of the present disclosure.
  • the different components making up the biophotonic compositions of the present disclosure may be provided in separate containers.
  • the block copolymer may be provided in a container separate from the chromophore.
  • Examples of such containers are dual chamber syringes, dual chamber containers with removable partitions, sachets with pouches, and multiple- compartment blister packs.
  • Another example is one of the components being provided in a syringe which can be injected into a container of another component.
  • the composition is provided in a spray can or bottle.
  • the kit may also comprise a systemic drug for augmenting the treatment of the thermosetting biophotonic compositions of the present disclosure.
  • the kit may include a systemic or topical antibiotic, hormone treatment (e.g. for acne treatment or wound healing), or a negative pressure device.
  • the kit may also comprise a means for applying the components of the thermosetting biophotonic compositions of the disclosure.
  • a container comprising a chamber for holding a thermosetting biophotonic composition, and an outlet in communication with the chamber for discharging the biophotonic composition from the container, wherein the thermosetting biophotonic composition comprises at least one chromophore solubilized in a block copolymer.
  • the chamber may be partitioned to separate ingredients which are unstable on mixing, such as an oxidant and the chromophore.
  • the container may further comprise a light source for activating the composition once discharged.
  • the kit may further comprise a light source such as a portable light with a wavelength appropriate to activate the chromophore of the thermosetting biophotonic composition.
  • a light source such as a portable light with a wavelength appropriate to activate the chromophore of the thermosetting biophotonic composition.
  • the portable light may be battery operated or re- chargeable.
  • thermosetting biophotonic compositions in accordance with the present disclosure may be included in the kit, or may be included on or associated with the containers comprising the compositions or components making up the thermosetting biophotonic composition of the present disclosure.
  • thermosetting biophotonic compositions are well within the skill of the ordinary practitioner and would require no more than routine experimentation, in light of the teachings of the present disclosure.
  • thermosetting composition comprising a poloxamer matrix incorporating therein chromophores.
  • Pluronic® F-127 was used which is a block copolymer of polyethylene glycol (PEG) and polypropylene glycol (PPG) (having a repeating unit comprising a PPG block linked to two PEG blocks), at a weight percentage which would allow it to thermoset to a cohesive biophotonic composition at temperatures between about 20°C and 39°C, e.g. when applied to a tissue or when applied to a tissue and/or heated with a lamp.
  • thermosetting (gelation) behaviour of 20% w/v and 25 % w/v Pluronic F-127 solutions at different temperatures was evaluated.
  • the solutions were prepared by dissolving Pluronic F-127 in cold de-ionised water ( ⁇ 4°C).
  • 20% w/v Pluronic solutions 20g of the Pluronic F-127 powder was dissolved in 100 mL of cold water.
  • 25% w/v Pluronic F-127 solutions 25g of the Pluronic F-127 powder was dissolved in 100 mL of cold water.
  • the concentration of Pluronic F-127 is expressed in weight per volume of water.
  • thermosetting was reversible in that thermogelled composition could re-liquefy if the temperature was reduced to below its gelling temperature.
  • the solutions of Table 2 were placed into pump-sprays and could be sprayed onto a target tissue to form a gel on touching the target tissue (at around 37°C). They could be removed easily by washing or wiping. Alternatively, a cold absorbent composition could be placed on the gel to bring the gel back to liquid form and soak it into the composition.
  • the composition may be a sponge or a cloth. The composition needs only to be at a temperature below the gelling temperature of the gel.
  • the gels 1-3 of Table 2 When activated by blue light, the gels 1-3 of Table 2 absorbed and emitted light.
  • any other poloxamer can be used instead of Pluronic F-127 of this example, for example, P-123, L-122, L-61, L-121 and P-65, at weight percentages which would allow their gelation at or around body temperature, at or around skin temperature or lower.
  • Example 2 Biophotonic evaluation of the thermosetting biophotonic composition of Example 1
  • the emission spectra of gel 3 (comprising 0.01 wt% eosin Y + 0.01 wt% fluorescein) of Example 1 is shown in Figure 1 .
  • the emitted fluorescence was measured using a SP-100 spectroradiometer (SP-100, ORB Optronix) when illuminated for 5 minutes with a light having a peak wavelength of about 400-470 nm and a power density of about 30-150 mW/cm 2 .
  • SP-100 SP-100, ORB Optronix
  • Example 3 Modulation of IL6 and IL8 by HaCaT human keratinocytes by the thermosetting biophotonic composition of Example 2
  • thermosetting biophotonic composition of Example 2 was evaluated for its ability to modulate inflammation, specifically cytokines IL6 and IL8.
  • HaCaT human keratinocyte cells were used as an accepted in vitro model for assessing modulation of these inflammatory cytokines.
  • Excessive, uncontrolled inflammation is observed in many skin conditions as well as in wounds, and can be detrimental to a host such as by impairing wound healing processes. Therefore a down regulation of IL6 and IL8 secretion may be beneficial in wound healing as well as alleviating other conditions, such as eczema and psoriasis.
  • a non-toxic concentration of IFNy was used to modulate the secretion of IL6 and IL8 by the HaCaT cells.
  • Dexamethasone final concentration of 5uM was used as a positive control (strong inhibitor of pro-inflammatory cytokine production).
  • the potential toxic effect of light on HaCaT cells was assessed using an in vitro toxicology assay kit, XTT based, which is a spectrophotometric evaluation of viable cell number.
  • thermosetting biophotonic composition of Example 2.
  • the thermosetting biophotonic composition was positioned 5 cm above the cell cultures and illuminated with blue light having a peak wavelength between 400-470nm (average 460nm) and a power density of about 30-150 mW/cm 2 for 90 seconds.
  • Cytokine quantification was performed by cytokine ELISA on the culture supernatant 24 hours after illumination according to manufacturer instructions (DuoSet ELISA development kit from R&D Systems). The quantity of cytokine secreted was normalized to cell viability. No toxic effect was observed for all the test samples as measured by cell viability using a spectrophotometric evaluation of viable cell number 24 hours after treatment. All samples were screened in quadruplets. Three biological repetitions were performed for the tested membrane.
  • thermosetting biophotonic composition of Example 2 produced a downward modulation of IL6 and IL8 on the IFN ⁇ stimulated HaCaT cells.
  • Table 3 summarizes the light treatment being received by the cultured cells during the illumination time from the thermosetting biophotonic composition, together with the IL6 and IL8 expression after illumination. Table 3. Light treatment being received by the cultured HaCaT cells during the illumination time from the thermosetting biophotonic composition and the IL6 and IL8 modulation observed.
  • Example 4 Modulation of inflammation by the thermosetting biophotonic composition of Example 2
  • thermosetting biophotonic composition of Example 2 a Human Cytokine Antibody Array (RayBio C-Series, RayBiotech, Inc.) was performed.
  • Cytokines are broadly defined as secreted cell-cell signaling proteins and play important roles in inflammation, innate immunity, apoptosis, angiogenesis, cell growth and differentiation. Simultaneous detection of multiple cytokines provides a powerful tool to study cell activity. Regulation of cellular processes by cytokines is a complex, dynamic process, often involving multiple proteins.
  • thermosetting biophotonic composition The effect of light being transmitted through and from the thermosetting biophotonic composition on cytokine secretion profile in the culture medium by HaCaT cells was determined using Human Cytokine antibody Array (RayBio C-series from Raybiotech). In brief, HaCaT cells were illuminated as in Example 3. Supernatants were collected 24h post-illumination and incubated with arrayed antibody membranes according to the manufacturer instructions. Obtained signals were quantified with ImageJ software. For each experiment, the XTT assay was performed to normalize the quantity of cytokine secreted to the cell viability (cell viability was over 90% in all samples). All samples were done in quadruplets. The summary table below shows that treatment of the cells with thermosetting biophotonic composition can modulate the expression of proteins. Table 4.
  • thermosetting biophotonic composition of Example 2 allowed blue light penetration (up to 6 J/cm 2 of energy fluency delivered to the cells) and produced fluorescence within the green and yellow light spectrum (up to 0.3 J/cm 2 of energy fluency delivered to cells). The results revealed that this light can downregulate pro-inflammatory cytokines IL-6 and IL-8 in HaCaT cells.
  • thermosetting biophotonic composition of Example 2 can also negatively modulate pro-inflammatory cytokines (such as TNF alpha, IL6) and pro-inflammatory chemokines (such as MCP-3, TARC) production.
  • the thermosetting biophotonic composition could also downmodulate growth factors secretion (such as EGF, IGF-1, ANG, VEGF).
  • thermosetting biophotonic composition of the present disclosure may be useful in the inflammatory phase of wound healing, when fast resolution of this phase is desired, or in other inflammatory disorders.
  • DHF cells Human Dermal Fibroblasts (DHF) cells were used here as an in vitro model to study the effect of visible blue light in combination with a thermosetting biophotonic composition of the present disclosure to evaluate the effect on the secretion of collagen, a component of the extracellular matrix.
  • Collagen production may be useful, for example, in wound healing, as well as for other indications such as skin conditions and rejuvenation.
  • matrix-generating cells i.e. fibroblasts
  • MMPs matrix-generating cells
  • cytokine/growth factors by proliferating and synthesizing new extracellular matrix (ECM) which is composed of collagen I, III, and V, proteoglycans, fibronectin and other components.
  • ECM extracellular matrix
  • TGF-beta concurrently inhibits proteases while enhancing protease inhibitors, favoring matrix accumulation.
  • TGF ⁇ -1 A non-toxic concentration of TGF ⁇ -1 was added to the cells to mimic hyperproliferation conditions.
  • the potential toxic effect of light on HaCaT cells was assessed using an in vitro toxicology assay kit, XTT based, which is a spectrophotometric evaluation of viable cell number.
  • Cell cultures were illuminated with light emitted by and transmitted through the thermosetting biophotonic composition of Example 2.
  • the gel was positioned 5 cm above the cell cultures and illuminated with blue light having a peak wavelength between 400-470nm and a power density of about 30-150 mW/cm 2 for 5 minutes.
  • Vitamin C and TGFB1 was used as a positive control.
  • Sirius red is an elongated dye molecule which reacts with collagen (type I, II, V), binds to it and after several washes which remove free dye the bounded Sirius red is eluted with sodium hydroxide and quantified using a spectrophotometer. All samples were screened in quadruplets. Two biological repetitions were performed for each of tested matrices.
  • thermosetting biophotonic composition of Example 2 can stimulate collagen production.
  • a 4-fold increase in collagen production in DHF cell culture supernatant was observed compared to the untreated control.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)

Claims (9)

  1. Composition biophotonique thermodurcissable comprenant un copolymère bloc à une concentration supérieure à 20 % en poids par volume de la composition, le copolymère bloc comprenant au moins une séquence de polyéthylène glycol-propylène glycol (PEG-PG), polyéthylène glycol-acide polylactique (PEG-APL) ou polyéthylène glycol-poly(ε-caprolactone) (PEG-PCL), et au moins un colorant xanthénique choisi parmi l'éosine Y, l'érythrosine B, la fluorescéine, le rose Bengale et la phloxine B, solubilisés dans le copolymère bloc, l'au moins colorant xanthénique étant de 0,001 % à 3 % en poids de la composition, la composition biophotonique thermodurcissable étant sous forme liquide à 22 °C et thermodurcissable lors de l'exposition à la chaleur.
  2. Composition biophotonique thermodurcissable selon la revendication 1, dans laquelle le copolymère bloc comprend au moins une séquence de polyéthylène glycol-propylène glycol (PEG-PG).
  3. Composition biophotonique thermodurcissable selon la revendication 1, dans laquelle le copolymère bloc est un poloxamère.
  4. Composition biophotonique thermodurcissable selon l'une quelconque des revendications 1 à 3, comprenant en outre un stabilisateur choisi parmi la gélatine, l'hydroxyéthylcellulose (HEC), la carboxyméthylcellulose (CMC) et un agent épaississant.
  5. Composition biophotonique thermodurcissable selon la revendication 1, comprenant en outre un agent oxydant, dans laquelle l'agent oxydant est choisi parmi le peroxyde d'hydrogène, le peroxyde d'urée et le peroxyde de benzoyle.
  6. Procédé de traitement cosmétique des tissus, le procédé comprenant :
    l'application de la composition biophotonique thermodurcissable selon l'une quelconque des revendications 1 à 5 sur un tissu cutané cible ; et
    l'éclairage de la composition biophotonique thermodurcissable avec de la lumière présentant une longueur d'onde qui chevauche le spectre d'absorption de l'au moins un colorant xanthénique.
  7. Procédé selon la revendication 6, dans lequel le traitement cosmétique des tissus est choisi parmi un rajeunissement de la peau, un soin de la peau et une stimulation de la synthèse de collagène.
  8. Composition biophotonique thermodurcissable selon l'une quelconque des revendications 1 à 5 destinée à une utilisation dans l'un ou plusieurs parmi
    - le traitement d'une affection cutanée ; et
    - la stimulation de la cicatrisation des plaies.
  9. Composition biophotonique thermodurcissable destinée à une utilisation selon la revendication 8, dans laquelle l'affection cutanée est choisie parmi l'acné, l'eczéma, le psoriasis et la dermatite.
EP15805894.1A 2014-06-09 2015-06-09 Compositions biophotoniques thermodurcissables et utilisations correspondantes Active EP3151860B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462009869P 2014-06-09 2014-06-09
PCT/CA2015/050530 WO2015188271A1 (fr) 2014-06-09 2015-06-09 Compositions biophotoniques thermodurcissables et utilisations correspondantes

Publications (3)

Publication Number Publication Date
EP3151860A1 EP3151860A1 (fr) 2017-04-12
EP3151860A4 EP3151860A4 (fr) 2017-12-06
EP3151860B1 true EP3151860B1 (fr) 2021-03-24

Family

ID=54832659

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15805894.1A Active EP3151860B1 (fr) 2014-06-09 2015-06-09 Compositions biophotoniques thermodurcissables et utilisations correspondantes

Country Status (15)

Country Link
US (1) US20170112755A1 (fr)
EP (1) EP3151860B1 (fr)
JP (1) JP6768525B2 (fr)
KR (1) KR20170014000A (fr)
CN (1) CN106714837B (fr)
AR (1) AR100864A1 (fr)
AU (1) AU2015274201B2 (fr)
BR (1) BR112016028895A2 (fr)
CA (1) CA2951467C (fr)
IL (1) IL249397A0 (fr)
MX (1) MX2016016407A (fr)
RU (1) RU2016151724A (fr)
TW (1) TW201609181A (fr)
WO (1) WO2015188271A1 (fr)
ZA (1) ZA201608478B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130281913A1 (en) * 2012-04-20 2013-10-24 Klox Technologies Inc. Biophotonic compositions and methods for providing biophotonic treatment
AU2015240385B2 (en) 2014-04-01 2019-02-28 Klox Technologies Inc. Tissue filler compositions and methods of use
CA3037397A1 (fr) * 2016-09-23 2018-03-29 Klox Technologies Inc. Compositions et procedes biophotoniques destines a reduire la formation de cicatrice
EP3852806A4 (fr) * 2017-01-27 2022-12-28 Klox Technologies Inc. Procédés de photobiomodulation de processus biologiques utilisant la fluorescence générée et émise depuis une composition biophotonique ou d'un système biophotonique
WO2018201257A1 (fr) * 2017-05-04 2018-11-08 Klox Technologies Inc. Dispositifs biophotoniques absorbants et systèmes de cicatrisation de plaie
US10967197B2 (en) 2018-08-29 2021-04-06 Azulite, Inc. Phototherapy devices and methods for treating truncal acne and scars

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8663692B1 (en) * 1999-05-07 2014-03-04 Pharmasol Gmbh Lipid particles on the basis of mixtures of liquid and solid lipids and method for producing same
US6693093B2 (en) * 2000-05-08 2004-02-17 The University Of British Columbia (Ubc) Drug delivery systems for photodynamic therapy
CN1224424C (zh) * 2002-02-01 2005-10-26 发礮成生物科技有限公司 粘膜吸附性的热凝性医药载体组合物
US20040009212A1 (en) * 2002-01-30 2004-01-15 Pharma Power Biotec Co. Ltd. Mucoadhesive thermoresponsive medicament-carrier composition
US20040247624A1 (en) * 2003-06-05 2004-12-09 Unger Evan Charles Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility
CN101166429A (zh) 2005-04-13 2008-04-23 雪印乳业株式会社 营养组合物
US8648119B2 (en) * 2008-05-23 2014-02-11 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
EA024827B1 (ru) * 2008-11-07 2016-10-31 Клокс Текнолоджиз Инк. Комбинация оксиданта и фотоактиватора для заживления ран
CN102146200B (zh) * 2011-04-19 2012-08-22 复旦大学 一种基于化学交联凝胶颗粒的温敏性水凝胶及其制备方法
US20130281913A1 (en) 2012-04-20 2013-10-24 Klox Technologies Inc. Biophotonic compositions and methods for providing biophotonic treatment
CN102731981B (zh) * 2012-06-01 2014-08-27 华中科技大学 一种温度敏感性可注射混合水凝胶
US20170106013A1 (en) * 2014-06-04 2017-04-20 Klox Technologies Inc. Biophotonic hydrogels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
CN106714837A (zh) 2017-05-24
MX2016016407A (es) 2017-04-06
ZA201608478B (en) 2019-06-26
CA2951467C (fr) 2023-08-08
AR100864A1 (es) 2016-11-09
WO2015188271A1 (fr) 2015-12-17
TW201609181A (zh) 2016-03-16
EP3151860A4 (fr) 2017-12-06
JP2017517537A (ja) 2017-06-29
CA2951467A1 (fr) 2015-12-17
BR112016028895A2 (pt) 2017-08-22
KR20170014000A (ko) 2017-02-07
IL249397A0 (en) 2017-02-28
AU2015274201A1 (en) 2016-12-22
JP6768525B2 (ja) 2020-10-14
RU2016151724A (ru) 2018-07-09
US20170112755A1 (en) 2017-04-27
CN106714837B (zh) 2021-04-16
EP3151860A1 (fr) 2017-04-12
AU2015274201B2 (en) 2020-06-25

Similar Documents

Publication Publication Date Title
US11723854B2 (en) Biophotonic compositions and methods for providing biophotonic treatment
US20190133908A1 (en) Chromophore combinations for biophotonic uses
US20170106013A1 (en) Biophotonic hydrogels
EP3151860B1 (fr) Compositions biophotoniques thermodurcissables et utilisations correspondantes
US11116841B2 (en) Biophotonic compositions, kits and methods
EP3151861B1 (fr) Compositions biophotoniques à base de silicone et leurs utilisations
CA2883717A1 (fr) Combinaison de chromophores a usages biophotoniques

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20170104

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20171108

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/352 20060101ALI20171102BHEP

Ipc: A61K 8/49 20060101ALI20171102BHEP

Ipc: A61Q 19/08 20060101ALI20171102BHEP

Ipc: A61K 47/34 20170101ALI20171102BHEP

Ipc: A61K 9/06 20060101ALI20171102BHEP

Ipc: A61P 17/02 20060101ALI20171102BHEP

Ipc: A61N 5/067 20060101ALI20171102BHEP

Ipc: A61P 17/06 20060101ALI20171102BHEP

Ipc: A61N 5/06 20060101ALI20171102BHEP

Ipc: A61K 8/73 20060101ALI20171102BHEP

Ipc: A61K 8/04 20060101ALI20171102BHEP

Ipc: A61K 8/90 20060101ALI20171102BHEP

Ipc: A61K 9/00 20060101ALI20171102BHEP

Ipc: A61K 8/22 20060101ALI20171102BHEP

Ipc: A61K 31/77 20060101ALI20171102BHEP

Ipc: A61K 41/00 20060101AFI20171102BHEP

Ipc: A61P 17/10 20060101ALI20171102BHEP

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1236400

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20190116

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20200131

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

INTC Intention to grant announced (deleted)
GRAR Information related to intention to grant a patent recorded

Free format text: ORIGINAL CODE: EPIDOSNIGR71

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

INTG Intention to grant announced

Effective date: 20210216

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1373801

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210415

Ref country code: DE

Ref legal event code: R096

Ref document number: 602015067258

Country of ref document: DE

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210624

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210625

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210624

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20210324

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1373801

Country of ref document: AT

Kind code of ref document: T

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210726

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210724

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602015067258

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

26N No opposition filed

Effective date: 20220104

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20210630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210609

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210630

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210609

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210724

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20150609

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230512

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230628

Year of fee payment: 9

Ref country code: DE

Payment date: 20230629

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20230627

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20210324